This application is a proposal for the competitive renewal of a K02 grant to support the career development plan of the candidate. The candidate research career is directed toward developing novel brain imaging methods to better characterize neurochemical alterations associated with schizophrenia, the clinical correlates of these alterations, and their relevance to treatment strategies. The candidate previous research experience included postmortem analysis of neurochemical markers in schizophrenic brains (NIMH) and neuroreceptor imaging using single photon computerized tomography (SPECT) (Yale University). The first cycle of this K02 (July 1998 to June 2003) was awarded after the candidate moved to Columbia University in 1996. The primary objective of the first cycle of this K02 was to develop expertise in a brain imaging modality that was new to him, Positron Emission Tomography (PET). In the next cycle of this grant, the candidate will continue to enhance his knowledge of PET, and will also develop expertise in nonhuman primate models of schizophrenia. The long-term goals of the candidate is to use neurochemical imaging as a translational research tool, involving both animal and clinical studies, to characterize neurotransmitter imbalances implicated in schizophrenia. In previous studies, the candidate observed that schizophrenia is associated with an increase in striatal amphetamine-induced DA release. The same dysregulation was induced in healthy volunteers by acute administration of the N-methyl-D-aspartate (NMDA) antagonist, ketamine, suggesting that alterations of DA function in schizophrenia might be secondary to disruptions of glutamate-mediated pathways. The current research plan proposes to: 1) develop a novel imaging method enabling detailed mapping ofpresynaptic DA function in nigro-striatal, mesolimbic and mesocortical DA systems, using the new PET tracer [lsF]fallypride and high resolution PET (specific aims 1 and 2); 2) use this technique to probe these DA systems in patients with schizophrenia, to test the hypothesis that schizophrenia is associated with increased mesolimbic DA function (specific aim 3); 3) use this technique to study, in nonhuman primates, the effect of subchronie phencyclidine (PCP) exposure on DA systems. The hypothesis is that chronic disruption of NMDA transmission by PCP will induce a pattern of DA dysregulations similar to that observed in schizophrenia. Ultimately, better understanding of these dysregulations and their origin will lead to improved treatment strategies. [unreadable] [unreadable]